Optically active esters and acids, such as (C&gt;3) alkyl chroman-2-carboxylates and chroman-2-carboxylic acid, having a single chiral center located on the carbon in the 2-position of the chroman structure and adjacent to the carboxyl group are useful as precursors in the chemical synthesis of certain pharmaceutical compounds. For example, compounds of the general formula (II) below, as described in European Patent 0546388 to AG Bayer, provide utility in the treatment of numerous central nervous system and cardiovascular diseases. ##STR2## Compounds (II), wherein R" is hydrogen or methoxy, contain a single chiral center at the 2-position of the chroman structure and are synthesized by the reaction of alkyl chroman-2-carboxylate or chroman-2-carboxylic acid precursors in an intermediate step. Alkyl as used herein encompasses linear, branched, and cyclic hydrocarbon residues of 1 to 20 carbons; (C&gt;3) alkyl refers to the subset of alkyl having 4 to 20 carbons.
The administration of an optically pure pharmaceutical compound (II) synthesized from an enantiomer of the (C&gt;3) alkyl chroman-2-carboxylate or chroman-2-carboxylic acid intermediate may provide an improvement over the administration of the racemic compound. Often when administering a racemic compound, one enantiomer may actually provide the beneficial effects while the opposite enantiomer may be deleterious or inert. Thus, advantages associated with the administration of the racemic mixture may be retained by using a single enantiomer of the compound without accompanying adverse side effects. Resolution of the racemic (R, S)-carboxylate or acid intermediate into its individual enantiomers is a convenient point in the overall synthetic route to the corresponding optically pure pharmaceutical compounds (II) at which to introduce desired stereochemistry.
Therefore, separation of the enantiomers is desirable, and a need exists for a convenient and economic method for producing the enantiomers which can be performed on a commercial scale. Resolution of the racemic carboxylate mixture into isolated enantiomers provides such a method and permits large-scale syntheses of the individual enantiomers.
Resolution of racemic mixtures of chiral compounds can often be achieved by subjecting the racemates to the stereoselective action of various enzymes. Generally, enzymes for use in resolutions should exhibit a high degree of stereoselectivity for catalyzing the reaction of one isomer to the exclusion of others. Enzymatic resolution by enantioselective hydrolysis of various ester compounds has been widely employed for the lab-scale, preparative-scale, and industrial-scale production of many optically pure acids and esters.
One class of enzymes, the hydrolases, which includes lipases, proteases, and esterases, for example, is often used in the resolution of enantiomers because they are commercially available at reasonable cost, they do not require expensive cofactors, and some exhibit reasonable tolerance to organic solvents. Additionally, hydrolases are known to stereoselectively catalyze the hydrolysis of certain carboxylic acid derivatives, including esters.
For example, Urban (U.S. Pat. No. 5,089,637) employed enzymatic hydrolysis using a microbial esterase derived from Pseudomonas fluorescens to resolve racemic mixtures of (C.sub.1 -C.sub.3) alkyl chroman-2-carboxylates. The esterase catalyzes stereoselective hydrolysis of the S-carboxylate enantiomer to produce a mixture of optically pure (C.sub.1 -C.sub.3) alkyl (R)-chroman-2-carboxylate and (S)-chroman-2-carboxylic acid.
However, resolution of the enantiomers of (C&gt;3) alkyl chroman-2-carboxylates by stereoselective enzymatic hydrolysis has not heretofore been described. Such a resolution is desirable in order to provide optically pure (C&gt;3) alkyl chroman-2-carboxylates and corresponding acids for use as synthetic precursors in the manufacture of optically pure pharmaceutical compounds (II) having the desired R- or S- stereochemistry.
Therefore, a need exists for an inexpensive and efficient method for producing on a commercial scale the individual enantiomers of (C&gt;3) alkyl chroman-2-carboxylates and chroman-2-carboxylic acid.